THE ALPHA(2) DOMAIN OF H-2D(D) RESTRICTS THE ALLELIC SPECIFICITY OF THE MURINE NK CELL INHIBITORY RECEPTOR LY-49A

Mouse NK lymphocytes express Ly-49 receptors, which inhibit cytotoxici ty upon ligation by specific MHC I molecules on targets. Different mem bers of the lectin-like mouse Ly-49 receptor family recognize distinct subsets of murine H-2 molecules, but the molecular basis for the alle lic specificity of Ly-49 has not been defined. We analyzed inhibition of natural killing by chimeric MHC I molecules in which the alpha(1), alpha(2), or alpha(3) domains of the Ly-39A-binding allele H-2D(d) wer e exchanged for the corresponding domains of the nonbinding allele H-2 D(b). Using the Ly-49A-transfected rat NK cell line, RNK-mLy-49A,9, we demonstrated that the H-2D(d) alpha(2) domain alone accounts for alle lic specificity in protection of rat YB2/0 targets in vitro. We also s howed that the H-2D(d) alpha(2) domain is sufficient to account for th e allele-specific in vivo protection of H-2(b) mouse RBL-5 tumors from NK cell-mediated rejection in D8 mice, Thus, in striking contrast to the alpha(1) specificity of Ig-like killer inhibitory receptors for hu man HLA, the lectin-like mouse Ly-49A receptor is predominantly restri cted by the H-2D(d) alpha(2) domain in vitro and in vivo.